The invention relates generally to anti-inflammatory drugs, and more particularly to novel compounds which inhibit the activity of cyclooxygenase-2.
The metabolites of arachidonic acid, such as prostaglandins, lipoxygenases and thromboxane products are produced in a wide variety of tissues and play a key role in several biological responses. Prostaglandins mediate both beneficial and undesirable biological reactions. The production of prostaglandins induces pain, swelling, heat and redness which are characteristic features of inflammation. The chronic inflammation associated with prostaglandin production leads to the breakdown of the injured tissue and angiogenesis. In pathologic chronic inflammation, normal tissues can be destroyed and the new blood vessel formation can support growth of abnormal tissue. Prostaglandins are also important for normal physiological processes in different organs. In the stomach, prostaglandins protect mucosa from acid. They also regulate blood flow and salt-water balance in the kidney. Prostaglandins are also important in platelets aggregation and participate in memory and other cognitive functions.
Prostaglandins are produced from cell membrane phospholipids by a cascade of enzymes. The enzymatic activities involve release of arachidonic acid from the cell membrane by phospholipase A2, followed by the conversion of arachidonic acid to a common prostaglandin precursor, PGH2, by cyclooxygenase (also called prostaglandin H synthase). PGH2 is finally converted to various types of prostaglandins (PGE1, PGE2, PGI2 or prostacyclin, PGF2xcex1 and thromboxane) by cell-specific synthases.
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) block the formation of prostaglandins by inhibiting cyclooxygenase activity. They have analgesic, antipyretic and anti-inflammatory activities. However, chronic treatment with the available NSAIDs often leads to disruption of beneficial prostaglandin-mediated processes. The side effects associated with constant usage of NSAIDs include gastrointestinal (GI) irritation and formation of life-threatening GI ulcers.
A dramatic advance in the field of inflammation research came with discovery of multiple enzymes for each step of the prostaglandin synthase cascade. The research suggested that in some situations, such as inflammation, cyclooxygenase was inducible. The cyclooxygenase known at the time, cyclooxygenase-1 (COX-1), was clearly non-inducible or modulated by glucocorticoids. A second, inducible form of cyclooxygenase known as cyclooxygenase-2 (COX-2) was subsequently identified and cloned by several groups of investigators. COX-1 is the constitutive cyclooxygenase isoform and is mainly responsible for the synthesis of cytoprotective prostaglandins in the GI tract and the synthesis of thromboxane which triggers platelet aggregation in blood platelets. COX-2 is inducible and short lived except in the case of certain tumors where it is constitutively activated. COX-2 expression is stimulated in response to endotoxins, cytokines, hormones, growth factors and mitogens. These observations suggest that COX-1 and COX-2 serve different physiological and pathophysiological functions. Indeed, it has been suggested that COX-1 is responsible for endogenous basal release of prostaglanclins and hence is important to the physiological functions of prostaglandins such as GI integrity and renal blood flow. On the other hand, it has been suggested that COX-2 is mainly responsible for the pathological effects of prostaglandins, where induction of the enzyme occurs in response to inflammatory agents, hormones, growth factors and cytokines. See, U.S. Pat. No. 5,604,253, incorporated herein by reference, for a discussion of the advantages of selective COX-2 inhibition. Principally, a selective COX-2 inhibitor is expected to possess similar anti-inflammatory, antipyretic and analgesic properties to a conventional NSAID but with reduced potential for gastrointestinal toxicity, and a reduced potential for renal side effects.
The differential tissue distribution of COX-1 and COX-2 provides an approach to develop selective inhibitors for COX-2 with reduced effect on COX-1, thereby preventing gastric side effects.
A number of selective COX-2 inhibitors have been reported. These include diaryl heterocyclics (Penning etal., J. Med. Chem, 40,1347-1365 (1997); acetoxyphenyl alkyl sulfides (Kalgutkar et al., J. Med. Chem, 41, 4800-4818 (1998); methane sulfonanilides (Li et al., J. Med. Chem, 38, 4897-4905 (1995); and tricyclic inhibitor classes (Wilkerson et al., J. Med. Chem., 38, 3895-3901 (1995). U.S. Pat. No. 5,604,253 discloses N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors.
What is needed are additional COX-2 inhibitors, particularly compounds which selectively inhibit the cyclooxygenase activity of COX-2 over COX-1.
It is an object of the invention to provide compounds and pharmaceutical compositions thereof for inhibiting the biological activity of COX-2, in particular the cyclooxygenase activity of COX-2.
It is an object of the invention to provide for methods of treating disease conditions which are associated with undesired prostaglandin production and/or secretion.
It is an object of the invention to provide for the treatment of cyclooxygenase-mediated disorders.
It is an object of the invention to provide compounds which selectively inhibit COX-2 over COX-1.
It is an object of the invention to provide methods for synthesizing compounds of the invention and intermediates thereof.
These and other objects of the invention shall become apparent from the following disclosure.
Compounds of formula I, and pharmaceutically acceptable salts thereof, are provided 
wherein:
X is selected from the group consisting of C1-C6 trihalomethyl, preferably trifluoromethyl; C1-C6 alkyl; and an optionally substituted or di-substituted phenyl group of formula II: 
wherein:
R3 and R4 are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine and bromine; hydroxyl; nitro; C1-C6 alkyl, preferably C1-C3 alkyl; C1-C6 alkoxy, preferably C1-C3 alkoxy; carboxy; C1-C6 trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano;
Z is selected from the group consisting of substituted and unsubstituted aryl.
The carbon chains in the alkyl and alkoxy groups which may occur in the compounds of the invention may be straight or branched. The expression xe2x80x9cC1-C6 alkylxe2x80x9d thus extends to alkyl groups containing one, two, three, four, five or six carbons. The expression xe2x80x9cC1-C6 alkoxylxe2x80x9d thus extends to alkoxy groups containing one, two, three, four, five or six carbons.
The term xe2x80x9carylxe2x80x9d, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term xe2x80x9carylxe2x80x9d is intended to include not only aromatic systems containing only carbon ring atoms but also systems containing one or more non-carbon atoms as ring atoms. Such systems may be known as xe2x80x9cheteroarylxe2x80x9d systems. The term xe2x80x9carylxe2x80x9d is thus deemed to include xe2x80x9cheteroarylxe2x80x9d.
Preferred aryl groups Z include phenyl and heteroaryl, which may be substituted or unsubstituted. By xe2x80x9csubstitutedxe2x80x9d is meant any level of substitution, although mon- di- and tri-substitution are preferred. The substituents are independently selected. The substituents are preferably selected from the group consisting of halogen, particularly chlorine, fluorine and bromine; hydroxyl; nitro; C1-C6 alkyl, preferably C1-C3 alkyl, most preferably methyl; C1-C6 alkoxy, preferably C1-C3 alkoxy, most preferably methoxy; carboxy; C1-C6 trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano. Although mono-, di- and tri-substitution is preferred, full substitution, particularly when the aryl group is phenyl, is possible. According to one preferred embodiment, Z is phenyl, and is mono-, di-, tri-, tetra- or penta-substituted with halogen. The halogen atoms may be the same or different.
According to another embodiment, Z is an aryl group other than phenyl or substituted phenyl, and is particularly substituted or unsubstituted heteroaryl. Such heteroaryl radicals include, for example, pyridyl, particularly 2-, 3- and 4-pyridyl; thienyl, particularly 2- and 3-thienyl; furyl, particularly 2- and 3-furyl; indolyl, particularly 3-, 4-, 5-, 6-, and 7-indolyl; benzothienyl, particularly 3-, 4-, 5-, 6-, and 7-benzothienyl; benzofuryl, particularly 3-, 4-, 5-, 6-, and 7-benzofuryl; imidazolyl, particularly 2- and 5-imidazolyl; pyrazolyl, particularly 3- and 5-pyrazolyl; 2-thiazolyl; 2-benzothiazolyl; quinolinyl, particularly 2-, 3- and 4-quinolinyl; and 4-(2-benzyloxazolyl). Representative preferred substituted heteroaryl groups include 6-methyl-2-pyridyl, 5-halo-2-thienyl, 5-methyl-2-thienyl, 5-halo-2-furyl, 5-halo-3-furyl, 2,5-dimethyl-3-thienyl and 2,5-dimethyl-3-furyl.
According to one preferred embodiment of the invention, Z is an optionally 2- or 4-substituted (or 2-, 4-di-substituted) phenyl group of the formula III: 
wherein R1 and R2 are independently selected from the group consisting of hydrogen; halogen, particularly fluorine, bromine and chlorine; hydroxyl; nitro; C1-C6 alkyl; C1-C6 alkoxy; and carboxy.
According to another preferred embodiment, wherein X is optionally mono- or di-substituted phenyl according to formula II, R3 and R4 are independently selected from the group consisting of hydrogen, halogen, hydroxyl; nitro; C1-C6 alkyl, C1-C6 alkoxy and carboxy, most preferably hydrogen, fluorine, bromine, chlorine, C1-C3 alkyl, C1-C3 alkoxy, hydroxy and nitro. When R3 is hydrogen and R4 is other than hydrogen, the preferred ring attachment position of R4 is the 2- or 4- position, most preferably the 4-position. Where both R3 and R4 are other than hydrogen, the preferred positions of substitution are the 2- and 4-positions, or the 3- and 4-positions.
The invention is also directed to isolated optical isomers of compounds according to formula I or V. By xe2x80x9cisolatedxe2x80x9d means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. Preferably, the isolated isomer is at least about 80%, more preferably at least 90% pure, even more preferably at least 98% pure, most preferably at least about 99% pure, by weight.
The invention is also directed to novel intermediates of the formula 
where X and Z are defined as above.
The invention is also directed to methods for preparing the aforesaid novel intermediates. A method for preparing a compound of formula IV comprises
(a) reacting a ketone compound selected from the group consisting of
(i) 1,1,1-trihaloacetone, preferably 1,1,1-trifluoroacetone; and
(ii) a compound of the formula 
wherein X is C1-C6 alkyl, or a radical of the formula 
wherein R3 and R4 are defined above; with a compound of the formula 
wherein Z is selected from the group consisting of substituted and unsubstituted aryl; and
(b) isolating a compound according to formula IV from the reaction products. According to a preferred embodiment, the reaction temperature is maintained in the range of from about 15xc2x0 C. to about 30xc2x0 C., but higher temperatures are possible depending on the boiling points of the reactants.
An alternative method is provided for preparing the aforesaid intermediates of formula IV wherein X is trihalomethyl, preferably trifluoro-, tribromo-, or trichloromethyl. The method comprises:
(a) reacting diethyl methylphosponate with an N-phenyltrihaloacetimidoyl chloride and a compound of the formula 
wherein Z is selected from the group consisting substituted and unsubstituted aryl; and
(b) isolating a compound according formula IV wherein X is trihalomethyl from the reaction products.
According to another embodiment of the invention, a compound of the formula V is provided: 
wherein:
X is selected from the group consisting of trihalomethyl, C1-C6 alkyl, and a group of formula II: 
wherein:
R3 and R4 are independently selected from the group consisting of hydrogen; halogen; hydroxyl; nitro; C1-C6 alkyl; C1-C6 alkoxy; carboxy; C1-C6 trihaloalkyl; and cyano;
Z is substituted or unsubstituted aryl, preferably substituted or unsubstituted heteroaryl; and
R5 is selected from the group consisting of 
wherein R6 is C1-C6 alkyl and M is Na, K or Li; or a pharmaceutically acceptable salt thereof.
Methods are also provided for preparing compounds according to formula I, by reacting the formula IV intermediate, wherein X and Z are defined as above, with 4-sulfamyl phenyl hydrazine or salt thereof; and isolating a compound according to formula I from the reaction products.
The invention is also directed to a pharmaceutical composition of one or more compounds of formula I in combination with a pharmaceutically effective carrier.
According to yet another embodiment of the invention, a method for treating a cyclooxygenase-mediated disease is provided comprising administering an effective amount of a compound according to formula I to an animal in need of such treatment. The expression xe2x80x9canimalxe2x80x9d is inclusive of human beings.